| The complex molecular and cellular mechanisms underlying neuronal control of animal movement are not well understood. Locomotion of Caenorhabditis elegans is mediated by a neuronal circuit that produces coordinated sinusoidal movement. Here, we utilize this simple, yet elegant behavior to show that VAV-1, a conserved guanine nucleotide exchange factor for Rho-family GTPases, negatively regulates motor circuit activity and the rate of locomotion. While vav-1 is expressed in a small subset of neurons, we find that VAV-1 function is required in a single interneuron (ALA) to regulate motor neuron circuit activity. Furthermore, we show by genetic and optogenetic manipulation of ALA that VAV-1 is required for the excitation and activation of this neuron. We find that ALA signaling inhibits command interneuron activity by abrogating excitatory signaling in the command interneurons that is responsible for promoting motor neuron circuit activity. Together, these data describe a novel neuromodulatory role for VAV-1-dependent signaling in the regulation of motor circuit activity and locomotion.;Since the ALA neuron is known to regulate sleep-like behavioral quiescence (Van Buskirk and Sternberg, 2007), we then investigated whether VAV-1 plays a role in ALA-mediated quiescence behaviors. We found a novel role for VAV-1 in regulation of sleep-like behavioral quiescence; no Vav protein has thus far been implicated in sleep, in mammals or invertebrates. Interestingly, the role of VAV-1 in quiescence parallels its function in regulating locomotory speed in wakeful adult animals. We discovered that VAV-1 is required in ALA to inhibit activity of the command interneurons during endogenous quiescence behavior in order to suppress locomotion during sleep-like quiescence. Accordingly, we find that activating the command interneurons disrupts sleep-like quiescence, much like loss of VAV-1. In summary, our results show that VAV-1 is part of a novel neuronal circuit required for proper regulation of sleep-like quiescence, as well as locomotion of wakeful animals.;Fascinatingly, the functions of neuronal VAV-1 described here may be conserved in mammals, since Vav2-/- and Vav3-/- mice show sympathetic nervous system hyperactivity, as evidenced by heightened levels of catecholamines and elevated heart and breathing rates (Sauzeau et al., 2007; Sauzeau et al., 2006). Additionally, transcripts of these neuronal vav genes are expressed in brain regions that regulate sleep (Movilla and Bustelo, 1999). Aberrant neuronal activity underlies a number of neurological conditions and diseases, such as Alzheimer's disease, epilepsy, and schizophrenia. Similarly, adequate sleep is required for optimal health; various sleep/wake disorders affect human well-being and have socioeconomic consequences. Thus, in addition to providing novel contributions to the understanding of VAV-1 and ALA interneuron function in motor activity of C. elegans, our work may have significant impact on the study of vav genes in other animal models and ultimately, humans. |
